Evaluation of relatives at risk: If both pathogenic variants have been identified in an affected family member, molecular genetic testing can be used to clarify the genetic status of an at-risk relative in childhood so that appropriate early support and management can be provided.

Genetic counseling.

DFNB1 is inherited in an autosomal recessive manner. In each pregnancy, the parents of a proband have a 25% chance of having a deaf child, a 50% chance of having a hearing child who is a carrier, and a 25% chance of having a hearing child who is not a carrier. When the GJB2 pathogenic variants causing DFNB1 are detected in an affected family member, carrier testing for at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic diagnosis are possible.

Diagnosis

Suggestive Findings

Nonsyndromic hearing loss and deafness caused by biallelic pathogenic GJB2 variants (DFNB1) should be suspected in individuals with the following:

Note: (1) Hearing is measured in decibels (dB). The threshold or 0-dB mark for each frequency refers to the level at which normal young adults perceive a tone burst 50% of the time. Hearing is considered normal if an individual's thresholds are within 25 dB of normal thresholds. (2) Severity of hearing loss is graded as mild (26-40 dB), moderate (41-55 dB), moderately severe (56-70 dB), severe (71-90 dB), or profound (90 dB). The frequency of hearing loss is designated as low (<500Hz), middle (501-2,000 Hz), or high (>2,000 Hz) (see Hereditary Hearing Loss and Deafness Overview).

No related systemic findings identified by medical history and physical examination

Gene-targeted testing requires the clinician to determine which gene(s) are likely involved based on phenotypic data, while comprehensive genomic testing does not. Because of the overlapping phenotypes of the many causes of hereditary hearing loss and deafness, most individuals with hereditary hearing loss and deafness are diagnosed by one of two approaches: comprehensive genomic sequencing (recommended) or gene-targeted testing (to consider).

Genetic diagnostic rates in 1,119 sequentially accrued persons with hearing loss. No person was excluded based on phenotype, inheritance, or previous testing. Testing resulted in identification of the underlying genetic cause for hearing loss in 440 individuals (more...)

Note: (1) Genes included in available panels and the diagnostic sensitivity of the test used for each gene vary by laboratory and are likely to change over time [Shearer & Smith 2015]. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel provides the best opportunity to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests; detection of copy number variants must be included in hearing loss panels [Shearer et al 2014].

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Testing to Consider

Single-gene testing can be considered if a deafness-specific multigene panel is not available. However, performing sequence analysis of GJB2 alone is not cost-effective unless it is limited to persons with severe-to-profound congenital nonsyndromic hearing loss. Offering single-gene testing of GJB2 reflexively to everyone with congenital hearing loss without regard to the degree of hearing loss is not evidence based and not cost effective [Jayawardena et al 2015, Shearer & Smith 2015].

Percentages vary depending on ethnicity. Numbers in table reflect screening of a US population primarily of northern European ancestry.

4.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by Feldmann et al [2009]) may not be detected by these methods.

Clinical Characteristics

Clinical Description

Nonsyndromic hearing loss and deafness (DFNB1) is characterized by congenital (present at birth) non-progressive sensorineural hearing impairment. Intrafamilial variability in the degree of deafness is seen.

If an affected person has severe-to-profound deafness, an affected sib with the same GJB2 pathogenic variants has a 91% chance of having severe-to-profound deafness and a 9% chance of having mild-to-moderate deafness [Tennessee Department of Health 2005].

If an affected person has mild-to-moderate deafness, an affected sib with the same GJB2 pathogenic variants has a 66% chance of having mild-to-moderate deafness and a 34% chance of having severe-to-profound deafness [Tennessee Department of Health 2005].

In a large cross-sectional analysis of GJB2genotype and audiometric data from 1,531 individuals with autosomal recessive mild-to-profound nonsyndromic deafness (median age 8 years; 90% within age 0-26 years) from 16 countries, linear regression analysis of hearing thresholds on age in the entire study and in subsets defined by genotype did not show significant progression of hearing loss in any individual [Snoeckx et al 2005]. This finding is in concordance with prior studies [Orzan et al 1999, Löffler et al 2001]; however, progression of hearing loss cannot be excluded definitively given the cross-sectional nature of the regression analysis.

Although Snoeckx et al [2005] found a slight degree of asymmetry, the difference in pure tone average at 0.5, 1.0, and 2.0 kHz between ears was less than 15 dB in 90% of individuals.

Vestibular function is normal; affected infants and young children do not experience balance problems and learn to sit and walk at age-appropriate times.

Except for the hearing impairment, affected individuals are healthy; life span is normal.

Based on Snoeckx et al [2005]. See full text, Figure 3 for scatter diagrams showing the binaural mean pure tone average (PTA) at 0.5, 1, and 2 kHz (PTA0.5,1,2kHz) for each person within each genotype class, using individuals homozygous for the c.35delG allele as a reference group.

Nomenclature

DFNB with a suffix integer is used to designate loci for autosomal recessive nonsyndromic deafness.

Prevalence

DFNB1 accounts for approximately 50% of congenital severe-to-profound autosomal recessive nonsyndromic hearing loss in the United States, France, Britain, and New Zealand/Australia [Green et al 1999, Azaiez et al 2004, Angeli 2008]. Its approximate prevalence in the general population is 14:100,000, based on the following calculation: the incidence of congenital hereditary hearing impairment is 1:2,000 neonates, of which 70% have nonsyndromic hearing loss. Seventy-five to 80% of cases of nonsyndromic hearing loss are autosomal recessive; of these, 50% result from biallelic pathogenic variants in GJB2. Thus, 5:10,000 x 0.7 x 0.8 x 0.5 = 14:100,000.

Given the extreme heterogeneity of autosomal recessive nonsyndromic hearing impairment, it is not surprising that epidemiologic studies in other populations have shown that the frequency of biallelicGJB2 pathogenic variants as a cause of hearing impairment is highly variable. For example, among families segregating autosomal recessive nonsyndromic hearing impairment, GJB2 variants are causally related to congenital hereditary hearing impairment in:

Hystrix-like ichthyosis-deafness (HID) syndrome (OMIM 602540) is a keratinizing disorder characterized by sensorineural hearing loss and hyperkeratosis of the skin. Shortly after birth, erythroderma develops, with spiky and cobblestone-like hyperkeratosis of the entire skin surface appearing by age one year. Severe palmoplantar keratoderma and scarring alopecia occur in some. HID syndrome is considered to differ from KID syndrome in: (1) the extent and time of occurrence of skin symptoms; (2) the severity of keratitis; and (3) electron microscopic features [van Geel et al 2002].

Vohwinkel syndrome (OMIM 124500) is a "mutilating" diffuse keratoderma because circumferential hyperkeratosis of the digits can lead to autoamputation. Mild-to-moderate sensorineural hearing loss is often associated with the disease [Maestrini et al 1999].

With some variants in GJB2, the epidermal disease and hearing loss cosegregate, while with other variants, the severity of the disease phenotype varies, suggesting that other factors modify gene expression [Kutkowska-Kaźmierczak et al 2015].

Other. A large deletion encompassing GJB2, the adjacent genes GJA3 and GJB6, and a portion of CRYL1 in trans with a GJB2pathogenic variant was identified in an individual with a contiguous gene syndrome characterized by profound prelingual hearing loss, mental and psychomotor development delay, clinodactyly of the second toes, and a frontal tuft [Feldmann et al 2009].

Clinical distinction between Usher syndrome types I & II: children w/type I usually delayed in walking until age 18 mos – 2 yrs (because of vestibular involvement); children w/type II usually begin walking at ~1 yr

Consider JLNS in any child w/congenital sensorineural deafness & negative DFNB1 testing – esp. w/a history of syncope or seizure or family history of sudden death before age 40 years

1.

Retinitis pigmentosa is a progressive bilateral symmetric degeneration of rod and cone functions of the retina.

2.

Pathogenic variants in genes at a minimum of nine different loci cause Usher syndrome type I. Genes at six of these loci – MYO7A (USH1B), USH1C, CDH23 (USH1D), PCDH15 (USH1F), USH1G, and CIB2 (USH1J) – have been identified.

3.

Pendred syndrome and DFNB4 comprise a phenotypic spectrum caused by biallelic pathogenic variants in SLC26A4 (the most common cause), or double heterozygosity in either SLC26A4 and FOXI1 or SLC26A4 and KCNJ10.

4.

Also called enlarged vestibular aqueduct (EVA)

5.

DVA with cochlear hypoplasia is known as Mondini malformation or dysplasia.

6.

Goitrous changes are typically not present at birth but do develop in early puberty (40%) or adulthood (60%).

7.

Treatment involves use of beta-adrenergic blockers, cardiac pacemakers, and implantable defibrillators as well as avoidance of drugs that cause further prolongation of the QT interval and of activities known to precipitate syncopal events.

Autosomal recessive nonsyndromic hearing loss without an identifiable GJB2 variant and with progression of hearing loss:

Management

Evaluations Following Initial Diagnosis

To establish the extent of involvement and needs in an individual diagnosed with nonsyndromic hearing loss and deafness caused by biallelic pathogenic variants in GJB2 (DFNB1), the following evaluations are recommended:

Recognition that, unlike with many clinical conditions, the management and treatment of severe-to-profound congenital deafness falls largely within the purview of the social welfare and educational systems rather than the medical care system [Smith et al 2005]

Surveillance

The following are appropriate:

Annual examination by a physician familiar with hereditary hearing impairment

Repeat audiometry to confirm stability of hearing loss

Agents/Circumstances to Avoid

Individuals with hearing loss should avoid environmental exposures known to cause hearing loss. Most important among these for persons with DFNB1 and mild-to-moderate hearing loss is avoidance of repeated overexposure to loud noises.

Evaluation of Relatives at Risk

If both GJB2 pathogenic variants have been identified in the proband, it is appropriate to clarify the genetic status of at-risk sibs shortly after birth so that appropriate early support and management can be provided to the child and family.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with
information on the nature, inheritance, and implications of genetic disorders to help them
make informed medical and personal decisions. The following section deals with genetic
risk assessment and the use of family history and genetic testing to clarify genetic
status for family members. This section is not meant to address all personal, cultural, or
ethical issues that individuals may face or to substitute for consultation with a genetics
professional. —ED.

Related Genetic Counseling Issues

Communication with individuals who are members of the Deaf community and who sign requires the services of a skilled interpreter.

Members of the Deaf community may view deafness as a distinguishing characteristic and not as a handicap, impairment, or medical condition requiring a "treatment" or "cure," or to be "prevented."

Many deaf people are interested in obtaining information about the cause of their own deafness, including information on medical, educational, and social services, rather than information about prevention, reproduction, or family planning.

The use of certain terms is preferred: probability or chance vs risk; deaf and hard-of-hearing vs hearing impaired. Terms such as "abnormal" should be avoided.

Family planning

The optimal time for clarification of carrier status and discussion of the availability of prenatal testing is before pregnancy.

It is appropriate to offer genetic counseling to young adults who are deaf or who may be carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes and allelic variants will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the GJB2 pathogenic variants have been identified in a family member with DFNB1, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis for DFNB1 are possible.

Many deaf individuals are interested in obtaining information about the underlying etiology of their hearing loss rather than information about reproductive risks. It is, therefore, important to ascertain and address the questions and concerns of the family/individual. "In contrast to the medical model which considers deafness to be a pathologic condition, many deaf people do not consider themselves to be handicapped but define themselves as being part of a distinct cultural group with its own language, customs, and beliefs. Strategies for effective genetic counseling to deaf people include the recognition that perception of risk is very subjective and that some deaf individuals may prefer to have deaf children." — from Arnos et al [1991]

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella
support organizations and/or registries for the benefit of individuals with this disorder
and their families. GeneReviews is not responsible for the information provided by other
organizations. For information on selection criteria, click here.

Data are compiled from the following standard references: gene from
HGNC;
chromosome locus from
OMIM;
protein from UniProt.
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
here.

Table B.

OMIM Entries for Nonsyndromic Hearing Loss and Deafness, DFNB1 (View All in OMIM)

Introduction

Gap junction channels are permeable to ions and small metabolites with relative molecular masses up to approximately 1.2 kd [Harris & Bevans 2001]. Differences in ionic selectivity and gating mechanisms among gap junctions reflect the existence of more than 20 different connexin isoforms in humans. Most connexin genes have a common architecture, with the entire coding region contained in a single large exon separated from a non-coding exon by an intron of variable size. The gap junction protein connexin 26 is encoded by GJB2.

Gene structure. The coding sequence of GJB2 (exon 2) encodes a 226-amino-acid protein. For a detailed summary of gene and protein information, see Table A, Gene.

~232-kb deletion (known as ∆GJB6-D13S1854)* that is also relatively common in the Spanish population (25% of DFNB1 alleles in deaf Spanish individuals not detected by GJB2sequence analysis or screening for the 309-kb deletion) [del Castillo et al 2005]

~131.4-kb deletion with a proximal breakpoint more than 100 kb upstream of the transcriptional start sites of GJB2 and GJB6; identified in a large German-American family with autosomal recessivecongenital severe-to-profound nonsyndromic sensorineural hearing loss [Wilch et al 2010]. This family is an example of a common and a rare pathogenic variant segregating in a non-consanguineous family comprising many individuals with an autosomal recessive disorder.

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1.

Variant designation that does not conform to current naming conventions

2.

IVS1+1G>A is -3179 nucleotides from the beginning of exon 2 in the genomic sequence (Reference Sequence NC_000013​.9)

3.

p.Met34Thr and p.Val37Ile are associated with normal hearing or mild hearing loss. See discussion in Pathogenic variants.

Normal gene product.GJB2 encodes connexin 26, a beta-2 gap junction protein composed of 226 amino acids. Connexins aggregate in groups of six around a central 2.3-nm pore to form a connexon. Connexons from adjoining cells covalently bond forming a channel between cells. Large aggregations of connexons called plaques are the constituents of gap junctions. Gap junctions permit direct intercellular exchange of ions and molecules through their central aqueous pores and permit synchronization of activity in excitable tissues and the exchange of metabolites and signal molecules in non-excitable tissues. Connexin 26 forms functional combinations with itself, connexin 32, connexin 46, and connexin 50.

Abnormal gene product.GJB2 pathogenic variants result in one of the following: